1. Field of the Invention
The present invention relates to cerebral function improving agents, more specifically, those agents which act by suppressing cerebral edema, protecting cerebral function, activating cerebral metabolism, or reducing the extent of cerebral infarction.
2. Description of the Prior Art
In recent years, an increasing number of individuals have suffered from cerebrovascular diseases or cerebral injury due to traffic accidents, etc. These conditions are often associated with cerebral edema and impairment of cerebral metabolism. This trend is probably due to dietary changes that have increased fat intake as well as the increased prevalence of cerebrovascular diseases along with the increase in the elderly population.
Cerebral edema, which impairs cerebral function, is defined as an increase in the water content of the brain parenchyma which results in an increase in cerebral volume. Cerebral edema not only causes transient metabolic and functional impairment of neurons but also increases the intracranial pressure, leading to impairment of the cerebral circulation and metabolism. These changes further aggravate cerebral edema, which may progress to brain herniation with an occasional fatal outcome.
Cerebral edema can be classified into two etiologic types, which are vasogenic edema and cytotoxic edema.
1. Vasogenic edema: Vasogenic edema occurs due to the interstitial retention of serum components leaking from vessels into the cerebral tissue as a result of dysfunction of the blood-brain barrier of the cerebral capillaries. Edema of this type is typically associated with cerebral contusion, tumor, abscess, or hemorrhage, and intracranial hematoma.
2. Cytotoxic edema: Cytotoxic edema results from cell membrane injury caused by lactate accumulation when energy metabolism is impaired in the cerebral parenchyma. Edema of this type is typically associated with cerebral ischemia, hypoxemia, and lactic acidosis.
The current therapeutic approaches to these conditions include:
(1) Intravenous hypertonic fluids: Hypertonic fluids relieve cerebral edema by increasing the blood osmotic pressure and thus attracting the interstitial fluid back into the vessels. However, a rebound phenomenon is observed after discontinuation of the hypertonic infusion because the blood osmotic pressure decreases again.
(2) Corticosteroids: Corticosteroids are used in the treatment of vasogenic edema associated with cerebral tumor or abscess because they promote the function of the blood-brain barrier, stabilize cell membranes, and suppress inflammatory responses and the production of cerebrospinal fluid. However, it has been reported that corticosteroids aggravate ischemic neuronal damage.
(3) Antioxidants: Antioxidants relieve cerebral edema by scavenging free radicals generated due to ischemia or cellular injury.
(4) Ca-channel blockers: Ca-channel blockers are expected to inhibit delayed neuronal death that results from calcium influx into cerebral neurons in the presence of edema. However, Ca-channel blockers have a vasodilatory effect, and thus may aggravate cerebral edema by increasing local blood flow.
(5) Barbiturates: Barbiturates protect the brain against ischemia because they reduce cerebral metabolic activity (cerebral oxygen and glucose consumption) and thus inhibit further lactate accumulation and acidosis. However, barbiturates exert these beneficial effects at doses which also cause respiratory depression and cardiovascular toxicity. Therefore, careful respiratory and circulatory management is required during their use.
Thus, there have been demands for development of drugs which are effective for the prevention and treatment of cerebral edema and have no potential for inducing a rebound response or other toxicities.
The present inventors have found that .beta.-hydroxybutyric acid, its salts, and its esters, which had not previously been evaluated for their effect on cerebral function, suppressed cerebral edema by activating cerebral metabolism. These compounds were also found to protect the brain mitochondria by activating cerebral metabolism and thus to reduce the extent of cerebral infarction caused by ischemia.
Therefore, the present invention provides cerebral function improving agents which specifically act by suppressing cerebral edema, protecting cerebral function, activating cerebral metabolism, or reducing the extent of cerebral infarction.